Form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine

ABSTRACT

The present invention relates to a novel crystalline form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine and methods for preparing the same.

PRIORITY CLAIM

The present application claims the benefit under 35 U.S.C. §371 ofInternational Application No.: PCT/IN02/00114 (published PCT applicationNo. WO 03/093222), filed Apr. 29, 2002, the entirety of which is herebyincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a novel crystalline form ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine and methods forpreparing the same.

BACKGROUND OF THE INVENTION

N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine has therapeuticutility in depressing blood glucose levels in the management of type 2diabetes mellitus.

N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine is disclosed inJapanese Patent Application No. 63-54321 (equivalent to EP-A-196222 andU.S. Pat. No. 4,816,484). This Japanese application describes how thecompound may be crystallized from aqueous methanol to yield crystalshaving a melting point of 129° C. to 130° C. These crystals are referredas “B-type”. These B-type crystals suffer from problems of instability,especially when subjected to mechanical grinding.

J. Med. Chem. 32, 1436 (1989) describes the preparation ofN-(cyclohexylcarbonyl)-D-phenylalanines and related compounds, includingN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.

U.S. Pat. Nos. 5,463,116 and 5,488,150 describe the preparation of anovel crystalline form ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine designated“H-type”. These patents also describe a method of treating form “B”crystals with appropriate solvent mixtures to obtain from “H” crystalsand vice-versa. The H-type crystals have an enhanced stability over Btype crystals.

Yaowu Fenxi Zazhi (2001), 21, 342 describes the “S” form of nateglinideas being different from form “B” and form “H”.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided a processfor the production of novel crystalline form “C” ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine by reactingD-phenylalanine methylester HCl with trans-4-isopropylcyclohexanecarboxylic acid in presence of propane phosphonic acid anhydride orLiOH—Al₂O₃ in a halogenated hydrocarbon solvent such as dichloromethaneor dichloroethane at a temperature between −10° C. to 90° C. followed bybase hydrolysis.

Alternatively, the product can be obtained by reactingtrans-4-isopropylcyclohexane carbonyl chloride with D-phenylalaninemethyl ester HCl in a halogenated hydrocarbon solvent such asdichloromethane or dichloroethane in presence of a base such astriethylamine or pyridine at a temperature between −10° C. to 90° C.followed by base hydrolysis.

According to a still further aspect of the present invention, the newcrystal from “C” ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine thus producedhas at least one, and preferably all, of the following properties:

-   -   (a) a melting point in the range of 126° C. to 132° C.;    -   (b) a powder X-ray diffraction pattern comprising characteristic        peaks at 14.0, 17.8, 19.0, 20.2 and 21.2±0.2 degrees measured at        reflection angle 2θ; and    -   (c) an infrared absorption spectrum comprising absorption bands        in the region of 1742, 1648, 1599, 1540 and 1191±2 cm⁻¹.

Yet another aspect of the invention includes form CN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine for use in thepreparation of a medicament for treating type 2 diabetes mellitus.

This invention also includes a pharmaceutical composition comprising atherapeutically effective amount of form CN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.

Another aspect of the invention relates to a method for treating apatient suffering from type 2 diabetes mellitus by administering to saidpatient a therapeutically effective amount of a pharmaceuticalcomposition of form CN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of form CN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine; and

FIG. 2 shows an infra red absorption spectrum of form C ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

According to one embodiment, the process for preparing form CN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine comprises thesteps of:

-   -   (a) suspending        N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl        ester in water or a water miscible solvent;    -   (b) treating the suspension with a base;    -   (c) adding water followed by adjusting the pH to 1.0-4.0 using a        mineral acid;    -   (d) extracting using ethyl acetate;    -   (e) concentrating the ethyl acetate extract;    -   (f) adding petroleum ether to the ethyl acetate concentrate; and    -   (g) filtering and drying the resulting precipitate to get form C        N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.

In certain embodiments, the water miscible solvent in step (a) above isselected from methanol, ethanol, isopropanol, or a mixture thereof. Inother embodiments, the water miscible solvent in step (a) above isselected from methanol.

In other embodiments, the base in step (b) above is selected frompotassium carbonate, sodium carbonate, sodium hydroxide, potassiumhydroxide, lithium hydroxide or a mixture thereof. In still otherembodiments, the base in step (b) above is potassium carbonate.

In certain embodiments, the precipitate obtained in step (g) above issuspended in water before filtration and drying to get form CN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.

In certain embodiments,N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester isprepared by:

-   -   (i) reacting D-phenylalanine methyl ester hydrochloride with        trans-4-isopropylcyclohexane carboxylic acid in a halogenated        hydrocarbon solvent;    -   (ii) filtering the reaction mixture; and    -   (iii) concentrating the resulting filtrate to get        N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl        ester.

In other embodiments, step (i) in the above process for the preparationof N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl esteris carried out in the presence of propane phosphonic acid anhydride,LiOH adsorbed onto aluminum oxide or triethylamine.

In still other embodiments, an alternate method for producingN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl estercomprises the steps of:

-   -   (i) reacting D-phenylalanine methyl ester hydrochloride with        trans-4-isopropylcyclohexane carbonyl chloride in a halogenated        hydrocarbon solvent and in the presence of a base;    -   (ii) filtering the reaction mixture; and    -   (iii) concentrating the resulting filtrate to get        N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl        ester.

In certain embodiments, the halogenated hydrocarbon solvent is selectedfrom dichloromethane or dichloroethane.

In other embodiments, the base is selected from triethylamine orpyridine.

In still other embodiments, the reaction temperature is −10° to 90° C.

Embodiments of the invention are illustrated below by way of thefollowing examples, which are not to be considered as limiting.

EXAMPLE 1

N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester(Method A): D-Phenylalanine methyl ester hydrochloride (10 g, 0.046 mol)was suspended in a solution of triethylamine (33 mL) in dichloromethane(50 mL). The mixture was cooled to 0-5° C. andtrans-4-isopropylcyclohexane carboxylic acid (7.9 g, 0.046 mol) wasadded. A solution of propane phosphonic acid anhydride (46.4 mL, 0.046mol) in ethyl acetate was added dropwise over a period of 30 minutes,maintaining the temperature at 0-5°. The resulting mixture was stirredfor 14 hours at ambient temperature. The reaction mixture was washedwith 1.5 N HCl, 5% sodium bicarbonate solution and brine. The organiclayer was concentrated to yield 12.5 g ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.

EXAMPLE 2

N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester(Method B): D-Phenylalanine methyl ester hydrochloride (20 g, 0.092 mol)was suspended in a solution of triethylamine (66 mL) in dichloroethane(100 mL) and the mixture was stirred for 1 hour at room temperature. Theorganic layer was separated after washing with water and dried overanhydrous sodium sulphate. Trans-4-isopropylcyclohexane carboxylic acid(15.8 g, 0.092 mol) was added to the organic layer followed byLiOH—Al₂O₃ (5.5 g of LiOH adsorbed on 40.5 g aluminum oxide) and theresulting mixture heated at for 24 hours. The reaction mixture wasfiltered through a celite bed and washed with 1.5 N HCl, 5% sodiumbicarbonate solution and brine. The organic layer was concentrated toyield 15.5 g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalaninemethyl ester.

EXAMPLE 3

N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester(Method C): D-Phenylalanine methyl ester hydrochloride (26 g, 0.12 mol)was suspended in a solution of triethylamine (85 mL) in dichloromethane(125 mL) and the mixture was cooled to 0-5° C. A solution oftrans-4-isopropylcyclohexane carbonyl chloride (25 g, 0.13 mol) indichloromethane (75 mL) was added dropwise over a period of 10 minuteswhile maintaining the temperature at 0-5° C. The resulting mixture wasstirred for 12 hours at ambient temperature then washed with 1.5 N HCl,5% sodium bicarbonate solution and brine. The organic layer wasconcentrated to yield 38 g ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.

EXAMPLE 4

Form C N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine: Tosuspension of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalaninemethyl ester (38 g, 0.11 mol) in methanol (600 mL) was added a solutionof potassium carbonate (80 g, 0.57 mol) in water (400 mL) and thereaction mixture stirred for 12 hours at ambient temperature. Water(1500 mL) was added and the pH was adjusted to 2.0 by adding 6N HCl. Themixture was extracted with ethyl acetate (3×400 mL) and the combinedextracts were washed with brine. The organic layer was concentrated toabout 150 mL then petroleum ether (300 mL) was added. The product wasfiltered and suspended in water (600 mL) and stirred for 12 hours atambient temperature. The slurry was filtered and dried to yield 35 g ofthe title compound. The compound showed a sharp melting point of128-129° C. X-ray diffraction pattern and infra red absorption spectrumof the final compound were recorded and identified as form C crystals ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.

1. Crystalline form “C”N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine having at leasttwo of the following properties: (a) a melting point in the range of126° to 132° C.; (b) a powder X-ray diffraction pattern comprisingcharacteristic peaks at 14.0, 17.8, 19.0, 20.2 and 21.2+0.2 degreesmeasured at reflection angle 2θ; and (c) an infrared absorption spectrumcomprising absorption bands in the region of 1742, 1648, 1599, 1540 and1191+2 cm⁻¹.
 2. Crystalline form “C”N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine having at leastone of the following properties: (a) a powder X-ray diffraction patternin accordance with FIG. 1; and (b) an infrared absorption spectrum inaccordance with FIG.
 2. 3. A process for preparing form “C”N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine comprising thesteps of: (a) suspendingN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester inwater or a water miscible solvent; (b) treating the suspension with abase; (c) adding water followed by adjusting the pH to 1.0-4.0 using amineral acid; (d) extracting using ethyl acetate; (e) concentrating theethyl acetate extract; (f) adding petroleum ether to the ethyl acetateconcentrate; and (g) filtering and drying the resulting precipitate toget form “C” N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine. 4.The process of claim 3, wherein the water miscible solvent in step (a)is selected from the group consisting of methanol, ethanol, isopropanol,and a mixture thereof.
 5. The process of claim 4, wherein the watermiscible solvent in step (a) is methanol.
 6. The process of claim 3,wherein the base in step (b) is selected from the group consisting ofpotassium carbonate, sodium carbonate, sodium hydroxide, potassiumhydroxide, lithium hydroxide and a mixture thereof.
 7. The process ofclaim 6, wherein the base in step (b) is potassium carbonate.
 8. Theprocess of any one of claims 3-7, further comprising the step ofsuspending the precipitate obtained in step (g) in water beforefiltering and drying to get form “C”N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.
 9. The processof claim 3, wherein theN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester ofstep (a) is prepared by: (i) reacting D-phenylalanine methyl esterhydrocholoride with trans-4-isopropylcyclohexane carboxylic acid in ahalogenated hydrocarbon; (ii) filtering the reaction mixture; and (iii)concentrating the resulting filtrate to getN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.10. The process of claim 9, wherein said halogenated hydrocarbon solventis selected from the group consisting of dichloromethane anddichloroethane.
 11. The process of claim 9, wherein step (i) is carriedout in the presence of propane phosphonic acid anhydride, LiOH adsorbedonto aluminum oxide or triethylamine.
 12. The process of claim 3,wherein the N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalaninemethyl ester of step (a) is prepared by: (i) reacting D-phenylalaninemethyl ester hydrochloride with trans-4-isopropylcyclohexane carbonylchloride in a halogenated hydrocarbon solvent and in the presence of abase; (ii) filtering the reaction mixture; and (iii) concentrating theresulting filtrate to getN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.13. The process of claim 12, wherein said halogenated hydrocarbonsolvent is selected from the group consisting of dichloromethane anddichloroethane.
 14. The process of claim 12, wherein said base isselected from the group consisting of triethylamine and pyridine. 15.The process of either of claims 9 or 12, wherein the reactiontemperature is −10° to 90° C.
 16. Crystalline form “C”N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine having at leasttwo of the following properties: (a) a melting point in the range of126° to 132° C.; (b) a powder X-ray diffraction pattern comprisingcharacteristic peaks at 14.0, 17.8, 19.0, 20.2 and 21.2+0.2 degreesmeasured at reflection angle 2θ; and (c) an infrared absorption spectrumcomprising absorption bands in the region of 1742, 1648, 1599, 1540 and1191+2 cm⁻¹; obtained by the process of: (i) suspendingN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester inwater or a water miscible solvent; (ii) treating the suspension with abase; (iii) adding water followed by adjusting the pH to 1.0-4.0 using amineral acid; (iv) extracting using ethyl acetate; (v) concentrating theethyl acetate extract; (vi) adding petroleum ether to the ethyl acetateconcentrate; and (vii) filtering and drying the resulting precipitate toget form “C” N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.